1. Field of the Invention
The present invention relates to new substituted .omega. phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl! alkyl, alkenyl or alkynyl!amine carboxamides, sulfonamides and phosphonylamides which are useful as antiarrhythmic agents.
2. Background of the Invention
Antiarrhythmic agents are classified in one of four categories, sodium channel blockers (Class I), calcium channel blockers (Class II), potassium channel blockers (Class III) and .beta.-adrenergic blockers (Class IV) based upon their ability to exhibit clearly definable pharmacological actions. Compounds contained in the present invention produce a homogenous prolongation of repolanzation and refractoriness which is indicative of Class III antiarrhythmic activity. The electrophysical mechanism underlying the prolongation of repolarization is known to be the blockade of currents through cardiac potassium channels. In contrast, Class I antiarrhythmic agents mediate their pharmacological effect through sodium channel blockade. In canine Purkinje fibers and papillary muscle preparations, the Class III antiarrhythmic action of quinidine is manifested by the prolongation of action potential duration (APD). The prolongation of the APD and the effective refractory period (ERP) has also been shown with other Class III antiarrhythmic agents such as d-sotalol (N-4-1-hydroxy-2-(1-methylethyl)amino!ethyl!phenyl!methanesulfonamide), dofetilide (4'-(2-methyl4-(methylsulphonylamino)phenethyl!amino!ethoxy)methanesulph onanilide), and E-4031 (1-2-(2-methylpyridin-6-yl)ethyl!-4-(4-methanesulfonylamino-benzoyl)-pipe ridine) which have shown pharmacological effects in clinical studies. The increase in APD in cardiac muscle has thus become an in vitro standard measure for putative Class III antiarrhythmic agents.
Class III antiarrhythmic activity is established as a viable therapeutic strategy for the management of ventricular arthythmias and the prevention of sudden cardiac death. Some recent reviews of Class III agents include: Gibson and Kersten, Drug Dev. Res., 1990, 19: 173-185; Carmeliet, Fundam. Clin. Pharniacol. 1993, 7: 19-28; Harrison and Bottorff, Advances in Pharmacology, 1992, 23: 179-215; Cimini and Gibson, Ann. Reports in Medicinal Chem. 1992, 27: 89-98.
Racemic sotalol is a structural prototype antiarrhythmic drug whose pharmacological activity stems from the blockade of the delayed rectifier subclass of potassium channels. Sotalol is a phenethanolamine derivative containing a methylsulfonamide moiety. Structural variations of this compound in which either chain extension by carbon or oxygen atoms or the addition of a second aryl moiety such as 4-phenoxyimidazole, have been achieved. However, the presence of a basic amine moiety within the original phenethyl chain has been retained. A general pharmacophore model for this class of compounds is defined and a generalized structure is proposed (Prog. Med. Chem. 1992, 29, 65) linking the structural ##STR1## variations; where Q is an electron withdrawing group, A is a one to four atom link between the aryl group and the nitrogen atom and the R.sub.1 and R.sub.2 substituents are selected from hydrogen, alkyl, arylalkyl or heteroarylalkyl groups.
The current invention is a departure from general Structure I, in that a carbonyl, sulfonyl or phosphoryl group is attached to the nitrogen (NH) atom. The current substituents change the physical chemical characteristics of the nitrogen atom (and therefore the pharmacophore) from one which is basic as in Structure I to one that has either neutral or acidic properties. This novel departure from the general pharmacophore defines a series of compounds which possess significant activity in the action potential prolongation procedure indicative of antiarrhythmic activity.